This proposed study is to advance our understanding of the molecular mechanism of nuclear Bcl-xL in tumor metastasis. B cell lymphoma 2 (Bcl-2) family proteins are known to play an important role in the control of apoptosis and the dysregulation in cancer. Bcl-xL is one of the anti-apoptotic members of the Bcl-2 family, frequently overexpressed in various cancer cells. It controls cellular commitment to apoptosis at the mitochondria and prevents cell death. Abrogating the anti-apoptotic activity of Bcl-xL as well as other anti- apoptotic Bcl-2 members as a putative target of cancer therapy has received significant research attention. Using an avian virus RCASBP-based in vivo mouse model for pancreatic neuroendocrine tumors (panNETs), we found that overexpression of Bcl-xL stimulates metastasis of primary panNETs without blocking apoptosis. We showed that ABT-737, a small molecular inhibitor of Bcl-xL, does not impair Bcl-xL-induced cell migration. We demonstrated that Bcl-xL promotes metastasis independent of its anti-apoptotic activity and its residence at the mitochondria in panNET cell lines as well as breast cancer cell line. We showed that nuclear- targeted Bcl-xL, not mitochondrial Bcl-xL nor Bcl-xL outside the nucleus, promotes EMT and tumor cell migration. Furthermore, Bcl-xL increases H3K4me3 on the promoter of TGF?1 to upregulate the expression, and TGF? neutralizing antibodies block the metastatic function of Bcl-xL in vitro. Based on our data, we hypothesize that the metastatic function of Bcl-xL is attributed primarily to its nuclear function. To test this hypothesis, we will use multiple experimental systems, which include Bcl-xL mutants, Bcl-xL knockout, doxycycline-inducible overexpression and shRNA, cancer cell lines, and mouse models for human cancer. The findings from cancer cells and mouse models will be cross-examined and the tests reciprocated. Information derived from this proposed study is expected to be useful in establishing the mechanisms by which Bcl-xL promotes metastasis, while providing significant insights into further development of drugs therapeutically targeting Bcl-xL in the treatment of metastatic cancers.